Pediatric oncology researchers have narrowed down a culprit in an aggressive form of the childhood cancer neuroblastoma that makes the disease progress once tumors form.
By mapping how DNA interacts with regulatory proteins that control transcription, part of the process by which DNA-encoded information carries out biological functions, the researchers pinpointed a precise variant in a single DNA base, guanine, that boosts LMO1 gene expression. The change in the LMO1 gene results in a “super-enhancer” that causes tumors to arise and grow out of control in an aggressive subtype of neuroblastoma, a cancer of the peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen.
“Cancers in general, and neuroblastoma in particular, have complex origins,” said John M. Maris, MD, a pediatric oncologist at The Children’s Hospital of Philadelphia, who is senior author of the study reported online in Nature. “It’s not common to discover causal gene variants in cancer, especially in a single base within the DNA sequence such as this.”
A change in a single base of DNA is called a single-nucleotide polymorphisms, or SNP. Previous research by Dr. Maris’ team showed that common SNPs within the LMO1 gene drive neuroblastoma susceptibility and progression by abnormally altering gene transcription. This new discovery increases the researchers’ understanding of how the specific protein that functions abnormally in LMO1-driven neuroblastoma sets in motion the molecular mechanisms fueling this high-risk subtype. Components on this biological pathway may offer attractive treatment targets.
“Drugs that inhibit other parts of the gene transcription machinery may offer potential novel treatments for this aggressive subset of neuroblastoma,” Dr. Maris said.
The researchers also found that another genetic change has a beneficial effect: If the DNA base at the specified location is a different letter of the genetic alphabet — thymine instead of guanine — it protects against neuroblastoma. Gene studies in human populations suggest that this protective gene variant evolved after human ancestors migrated out of Africa, hundreds of thousands of years ago.
Finding Genetic Predisposition to Childhood Cancers Raises New Challenges
Why some children develop cancer and not others remains an enormous question that Dr. Maris tackled in a recent editorial in the New England Journal of Medicine, “Defining Why Cancer Develops in Children.” The editorial reflects on a major pediatric study of cancer predisposition genes in the same issue of the journal.
A team from St. Jude Children’s Research Hospital led by James R. Downing, MD, found that 8.5 percent of children and adolescents with cancer in their sample of 1,120 patients had mutations known to raise their risk of cancer. In the majority of cases, a child's inherited cancer-predisposition mutation did not seem to lead to cancer in the parents or in other family members.
"More frequently than previously thought, children with cancer may have genes predisposing them to cancer, even when cancer doesn't show up in the child's family history," said Dr. Maris, who also is the Giulio D’Angio Chair in Neuroblastoma Research at CHOP and a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. "We need to better understand how other genes may interact with the original mutation to cause cancer in the child."
Dr. Maris discussed how advancements in genetic testing and genetic science have implications for counseling families as more become aware of these cancer-predisposition genes in both affected children and in their family members without cancer. In addition, because some cancer-related mutations may also increase the risk that a childhood-cancer survivor may later develop a second cancer, clinicians and cancer researchers will need to develop the most effective strategies for counseling patients from infancy through old age.
"Like all good research, this new study opens up more questions and areas for more investigation," Dr. Maris said. "At the very least, this work should remind clinicians that we need to look beyond family history in treating and counseling pediatric cancer patients and their families."